Berberine alpha-ketoglutarate salt, crystalline form, methods of preparation and applications thereof

Abstract

The present disclosure relates to berberine alpha-ketoglutarate salts, which can be used in a pharmaceutical or nutraceutical composition for the treatment or prevention of bacterial infections, cardiovascular diseases, or other conditions. The present disclosure also relates to crystalline forms, methods of preparing berberine alpha-ketoglutarate salts and applications thereof.

What is claimed is: 
     
       1. A berberine alpha-ketoglutarate salt in solid form having any one of the following chemical formulas: 
       
         
           
           
               
               
           
         
       
     
     
       2. The berberine alpha-ketoglutarate salt according to  claim 1 , wherein the salt is amorphous, crystalline, or a mixture thereof. 
     
     
       3. The berberine alpha-ketoglutarate salt according to  claim 1 , wherein the salt is an anhydrous form, solvate, hydrate, co-crystal, or a mixture thereof. 
     
     
       4. The berberine alpha-ketoglutarate salt according to  claim 1 , wherein the salt is a single crystalline form. 
     
     
       5. The berberine alpha-ketoglutarate salt according to  claim 1 , wherein the salt has a molar ratio of the berberine and the neutralized alpha-ketoglutaric acid from about 0.9:1 to about 1:0.9. 
     
     
       6. The berberine hydrogen alpha-ketoglutarate salt according to  claim 5 , wherein the salt is a crystalline solid. 
     
     
       7. The crystalline berberine hydrogen alpha-ketoglutarate salt according to  claim 5 , wherein the crystalline solid is an anhydrous form. 
     
     
       8. The crystalline form of berberine hydrogen alpha-ketoglutarate according to  claim 5 , wherein the salt is an anhydrous form and is characterized by an PXRD pattern comprising one or more peaks expressed as 2θ±0.2° of about 7.1°, about 8.4°, about 8.6°, about 14.1°, about 15.5°, about 16.8°, about 19.1°, about 19.5°, about 20.6°, and about 24.7°. 
     
     
       9. A composition comprising a berberine alpha-ketoglutarate salt according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       10. The composition according to  claim 9 , wherein the carrier is a diluent, adjuvant, excipient, vehicle, or mixture thereof. 
     
     
       11. The composition according to  claim 9 , wherein the composition is formulated into tablets, gelcaps, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels, hydrogels, oral gels, pastes, eye drops, ointments, creams, plasters, drenches, delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols. 
     
     
       12. The composition according to  claim 9 , wherein the composition is an immediate release composition or extended-release composition. 
     
     
       13. A single crystalline form of a berberine alpha-ketoglutarate salt that exhibits the following PXRD characteristics: triclinic P-1 space group, Z′=2, unit cell dimensions: a=11.7475(5) Å, b=14.2681(6) Å, c=15.2790(6) Å, α=101.394(1)°, β=102.756(1)°, γ=112.146(1)° and V=2198.9(2) Å 3 . 
     
     
       14. A method of preparing berberine hydrogen alpha-ketoglutarate according to  claim 1  comprises mixing a berberine acetone adduct and alpha-ketoglutaric acid at a temperature of from about 60 to about 80° C. 
     
     
       15. A method of preparing berberine hydrogen alpha-ketoglutarate according to  claim 1  from berberine hemi-sulfate by using a direct ion-exchange process comprising neutralizing a mixture solution of berberine hemi-sulfate and alpha-ketoglutaric acid with a base at a room temperature.